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Loss of the SMRT/NCoR2 Corepressor Correlates with JAG2 Overexpression in Multiple Myeloma

Departments of ¹ Cancer Genetics, ² Medicine, and ³ Molecular Targets and Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, New York; and ⁴ Laboratoire d'Hématologie, Institut de Biologie, Nantes Cedex 1, France

Requests for reprints: Asher A. Chanan-Khan, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-3221; Fax: 716-845-3894; E-mail: asher.chanan-khan{at}roswellpark.org.

Key Words: SMRT • JAG • Multiple Myeloma • B-cell

Multiple myeloma (MM) is a clonal B-cell neoplasm that accounts for 10% of all malignant hematologic neoplasms and that affects terminally differentiated B cells (i.e., plasma cells). It is now well recognized that the cytokine interleukin-6 (IL-6) is a major cytokine that promotes the proliferation of malignant plasma cells in MM. The IL-6 gene can be regulated by the NOTCH genes products. We have previously shown that the NOTCH ligand, JAG2, is overexpressed in MM. To investigate the mechanism(s) leading to JAG2 overexpression in MM, we assessed potential epigenetic modifications of the JAG2 promoter. We showed that the JAG2 promoter region is aberrantly acetylated in MM cell lines and patient samples. The acetylation state of histones is regulated by the recruitment of histone deacetylases (HDAC). HDACs are typically recruited to promoter regions through interaction with nuclear corepressors such as SMRT. SMRT levels were therefore investigated. Interestingly, MM cell lines and patient samples presented significantly reduced SMRT levels. The experiments suggest a correlation between constitutive acetylation of the JAG2 core promoter in the MM cell lines and reduced levels of the SMRT corepressor that recruits HDAC to promoter regions. Finally, SMRT function restoration induced JAG2 down-regulation as well as MM cell apoptosis. [Cancer Res 2009;69(10):4380–7]